EP1523571B1 - Sgk und nedd als diagnostische und therapeutische targets - Google Patents

Sgk und nedd als diagnostische und therapeutische targets Download PDF

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EP1523571B1
EP1523571B1 EP03732526A EP03732526A EP1523571B1 EP 1523571 B1 EP1523571 B1 EP 1523571B1 EP 03732526 A EP03732526 A EP 03732526A EP 03732526 A EP03732526 A EP 03732526A EP 1523571 B1 EP1523571 B1 EP 1523571B1
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sgk1
nedd4
sglt1
pkb
glucose
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EP1523571A2 (de
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Florian Physiologisches Institut I LANG
Michael Dieter
Karl Lang
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Lang Florian Physiologisches Institut I
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    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q1/00—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions
    • C12Q1/48—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving transferase
    • C12Q1/485—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving transferase involving kinase
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/06—Antihyperlipidemics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A61P5/38—Drugs for disorders of the endocrine system of the suprarenal hormones
    • A61P5/40—Mineralocorticosteroids, e.g. aldosterone; Drugs increasing or potentiating the activity of mineralocorticosteroids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A61P5/38—Drugs for disorders of the endocrine system of the suprarenal hormones
    • A61P5/44—Glucocorticosteroids; Drugs increasing or potentiating the activity of glucocorticosteroids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A61P5/48—Drugs for disorders of the endocrine system of the pancreatic hormones
    • A61P5/50—Drugs for disorders of the endocrine system of the pancreatic hormones for increasing or potentiating the activity of insulin
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01K—ANIMAL HUSBANDRY; AVICULTURE; APICULTURE; PISCICULTURE; FISHING; REARING OR BREEDING ANIMALS, NOT OTHERWISE PROVIDED FOR; NEW BREEDS OF ANIMALS
    • A01K2217/00—Genetically modified animals
    • A01K2217/05—Animals comprising random inserted nucleic acids (transgenic)
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2333/00—Assays involving biological materials from specific organisms or of a specific nature
    • G01N2333/90—Enzymes; Proenzymes
    • G01N2333/914—Hydrolases (3)
    • G01N2333/948—Hydrolases (3) acting on peptide bonds (3.4)
    • G01N2333/95—Proteinases, i.e. endopeptidases (3.4.21-3.4.99)
    • G01N2333/964—Proteinases, i.e. endopeptidases (3.4.21-3.4.99) derived from animal tissue
    • G01N2333/96425—Proteinases, i.e. endopeptidases (3.4.21-3.4.99) derived from animal tissue from mammals
    • G01N2333/96427—Proteinases, i.e. endopeptidases (3.4.21-3.4.99) derived from animal tissue from mammals in general
    • G01N2333/9643—Proteinases, i.e. endopeptidases (3.4.21-3.4.99) derived from animal tissue from mammals in general with EC number
    • G01N2333/96466—Cysteine endopeptidases (3.4.22)

Definitions

  • the present invention relates to a method for the in vitro diagnosis of predispositions to obesity, a diagnostic kit and antibodies.
  • the intestinal and renal transport of glucose is accomplished by the Na + -coupled transporter Sglt1 (sodium glucose transporter) in the apical membrane of the epithelial cells. If this glucose transport is disturbed, it can lead to various diseases such as obesity or diabetes mellitus.
  • Sglt1 sodium glucose transporter
  • Nedd4-2 is phosphorylated and inactivated by serum and glucocorticoid-inducible kinase 1 (Sgk1).
  • Sgk1 serum and glucocorticoid-inducible kinase 1
  • SNPs single nucleotide polymorphisms
  • kinases are proteins that transfer a phosphate group to individual substrates.
  • Serum and glucocorticoid-dependent kinase (Sgk) was originally cloned from rat breast carcinoma cells [ Webster MK, Goya L, Firestone GL, Y. Biol. Chem. 268 (16): 11482-11485, 1993 ; Webster MK, Goya L, Ge Y, Maiyar AC, Firestone GL, Mol. Cell. Biol. 13 (4): 2031-2040, 1993 ].
  • Sgk1 was originally cloned as a glucocorticoid-sensitive gene [ Webster MK, Goya L, Ge Y, Maiyar AC, Firestone GL: Characterization of Sgk, a novel member of the serine / threonine protein kinase gene family which is transcriptionally induced by glucocorticoids and serum. Mol Cell Biol 1993; 13: 2031-2040 ]. A number of studies revealed that Sgk1 is under the influence of a variety of stimuli [ Lang F, Cohen P. Regulation and physiological roles of serum and glucocorticoid-induced protein kinase isoforms. Science STKE.
  • Sgk serum- and glucocorticoid-regulated kinase
  • Sgk1 is stimulated by insulin like growth factor IGF1, insulin and oxidative stress via a signal cascade by phosphoinositol-3-kinase (PI3-kinase) and phosphoinositol-dependent kinase (Pdk1)
  • PI3-kinase phosphoinositol-3-kinase
  • Pdk1 phosphoinositol-dependent kinase
  • Sgk1 by Pdk1 involves phosphorylation at the serine of position 422. Mutation of this serine into an aspartate ( S422D Sgk1) results in a constitutively active kinase [ Kobayashi T, Cohen P: Activation of serum- and glucocorticoid-regulated protein kinase by agonists that activate phosphatidylinositide 3-kinase is mediated by 3-phosphoinositide-dependent protein kinase-1 (Pdk1) and pdk2. Biochem J 1999; 339: 319-328 ].
  • a method for the treatment or prophylaxis of obesity is known from WO 00/18918 A2 known.
  • the method is based on influencing the activity of Sglt2 (sodium dependent glucose cotransporter) via suitable antibodies or antisense oligonucleotides.
  • the aim of the invention is to provide new diagnostic applications for the regulation of glucose uptake.
  • Nedd4-2 also inactivates the renal and intestinal Na + glucose transporter Sglt and that this action is suppressed by Sgk1 and / or Sgk3 and / or PKB.
  • Sgk1 and / or Sgk3 and / or PKB play a causal role in the development of obesity.
  • the cause of obesity can be identified and treated or prevented by adequate therapeutic and prophylactic measures.
  • Obesity and hyperglycaemia which are triggered by accelerated intestinal glucose absorption, also favor the development of diabetes mellitus. Finally, simultaneous dysregulation of the renal Na + channels would lead to the development of hypertension. Obesity, hypertension and the development of diabetes mellitus are key findings of the so-called metabolic syndrome.
  • At least one substance is disclosed for the detection of the expression and / or function of activated Sgk1 and / or activated Sgk3, and / or activated PKB and / or inactive Nedd4-2.
  • the substance is at least one of the group of antibodies and / or nucleotides.
  • it may be an antibody which is directed against Sgk1, Sgk3, PKB and / or Nedd4-2, and in a detection method known in the art, such as.
  • B. ELISA enzyme-linked immunosorbent assay
  • the specific antibody directed against the antigen to be determined eg Sgk1, Sgk3 and / or PKB
  • a carrier substance eg cellulose, polystyrene
  • a labeled antibody is added to these immune complexes.
  • the immunocomplex-bound enzyme-substrate complexes can be visualized or the antigen concentration in the sample can be determined by photometric determination of the immune complex-bound marker enzymes by comparison with standards of known enzyme activity.
  • nucleotides in particular oligonucleotides
  • diagnostic detection which are suitable for example by means of the so-called polymerase chain reaction, via a molecular genetic method in which certain DNA segments are selectively amplified, a quantitative detection of for example, to provide Sgk1.
  • antibodies to at least one phosphorylated and / or non-phosphorylated Sgk1 consensus sequence are used in the Nedd 4-2 protein.
  • consensus sequence is meant the amino acid sequences that constitute the substrate site of the kinases, that is, the phosphorylation site (s).
  • inactivating mutations are detected in the Nedd4-2 protein, in particular in the Sgk1 consensus sequence (eg S338D Nedd4-2 or S444D Nedd4-2).
  • an activating mutation for example S422D Sgk1 and / or T308D, S473D PKB, is detected in the DNA of the patients.
  • corresponding mutations in the RNA of the patients are detected.
  • corresponding mutations are detected in the Sgk, in particular Sgk1 and / or Sgk3, PKB and / or in the Nedd protein, in particular in the Nedd4-2 protein of the patients.
  • Either suitable antibodies and / or suitable nucleotides, in particular oligonucleotides are preferably used as probes for these detections.
  • the diseases to be diagnosed which are associated with impaired glucose transport, are obesity.
  • the invention comprises a method for the in vitro diagnosis of predispositions to obesity.
  • This diagnostic procedure is characterized in that a polymorphism is detected in Sgk1.
  • the polymorphism E8CC / CT; I6CC in Sgk1 is detected.
  • This polymorphism is in direct correlation with the body mass index, so this is a particularly suitable marker to show predispositions to obesity.
  • the abbreviated notation stands for an SNP in exon 8 (C ⁇ T) and a second SNP 551 base pairs away from the donor site (intron 6) of exon 7 (T ⁇ C).
  • blood is preferably taken from corresponding experimental animals or patients, and the sequence determined at the appropriate place on the basis of the genetic material contained therein by appropriate sequencing or by other methods familiar to the person skilled in the art.
  • sequence determined at the appropriate place on the basis of the genetic material contained therein by appropriate sequencing or by other methods familiar to the person skilled in the art.
  • all other biological samples from which genetic material can be isolated are also suitable.
  • the use of at least one active ingredient for influencing the glucose transport, in particular the intestinal and / or renal glucose transport is disclosed.
  • at least partially the glucose transporter Sglt, in particular Sglt1 is responsible for this glucose transport.
  • the glucose transport can be influenced according to the invention.
  • the active ingredient is used to influence at least one Sgk, in particular Sgk1 and / or Sgk3, and / or PKB and / or an influence on at least one Nedd, in particular Nedd4-2.
  • the active ingredient is preferably directed against a Sgk, in particular a Sgk1 and / or Sgk3, and / or PKB and / or a Nedd, in particular Nedd4-2. Furthermore, the active ingredient against activators, inhibitors, regulators and / or biological precursors of a Sgk, in particular of Sgk1 and / or Sgk3, and / or PKB and / or a Nedd, in particular Nedd4-2.
  • the active ingredient is a polynucleotide.
  • This polynucleotide may comprise, for example, an antisense sequence which reduces or inhibits the expression of at least one of said proteins.
  • the polynucleotide encodes a peptide, preferably a polypeptide, this peptide having the expression and / or function of a Sgk, in particular Sgk1 and / or Sgk3, and / or PKB and / or a Nedd, in particular Nedd4-2, affected.
  • the active compound itself may preferably be a peptide or a polypeptide which influences the expression and / or function of said proteins.
  • the active ingredient may be a "small molecular compound", preferably a "small molecular compound” with a molecular weight ⁇ 1,000.
  • the active ingredient is intended to inhibit at least one Sgk, in particular Sgk1 and / or Sgk3, and / or PKB and / or stimulate at least one Nedd, in particular Nedd4-2 , be achieved.
  • Sgk and PKB are kinases, in particular known to those skilled kinase inhibitors such. As staurosporine and / or chelerythrine or at least one of its analogs in question. Because Nedd are ligases, ligase activators are suitable for their stimulation.
  • These active substances are preferably used for the production of a medicament or a pharmaceutical composition.
  • the metabolic syndrome in particular obesity.
  • the active ingredient is preferably stimulated at least one Sgk, in particular Sgk1 and / or Sgk3, and / or PKB and / or an inhibition of at least one Nedd, in particular Nedd4-2, achieved.
  • Stimulation of, for example, Sgk1 inhibits, for example, Nedd4-2, which in turn leads to delayed degradation of the glucose transporter Sglt1. This in turn leads to an increase in glucose transport.
  • the active ingredient is at least one Sgk and / or PKB activator, in particular a growth factor, preferably IGF1 and / or insulin.
  • the active substance is at least one stimulant for the transcription of sgk1 and / or sgk3 and / or a gene for PKB, preferably at least one glucocorticoid, mineralcorticoid, gonadotropin and / or cytokine, in particular TGF ⁇ .
  • the invention further relates to a diagnostic kit.
  • This comprises at least one substance for the detection of the expression and / or function of activated Sgk1 and / or activated Sgk3, and / or activated PKB and / or inactive Nedd4-2 for the diagnosis of obesity.
  • the kit may contain antibodies and / or oligonucleotides for detecting the corresponding proteins and / or nucleic acids. For example, this can be used to analyze the amount and / or the activity of the various proteins or enzymes. You can also continue corresponding mutations are detected in the genes.
  • this kit reference is made to the rest of the description.
  • the invention encompasses antibodies directed against at least one phosphorylated kinase consensus sequence in the Nedd4-2 protein.
  • This kinase consensus sequence is the sequence that is phosphorylated by Sgk1. With the help of such an antibody can be analyzed whether Nedd4-2 was phosphorylated by Sgk1 and thus inactivated. Thus, the activity status of Nedd4-2 can be examined.
  • the invention includes an antibody directed against the corresponding non-phosphorylated kinase consensus sequence in the Nedd4-2 protein. It is particularly preferred to combine the two antibodies according to the invention in a test arrangement with each other, whereby very meaningful results with respect to the activity status of Nedd4-2 can be achieved.
  • the invention encompasses antibodies directed against at least one mutant kinase consensus sequence in the Nedd4-2 protein. Again, this is the Sgk1 consensus sequence, which has been mutated accordingly. Particularly preferred mutants here are S338D Nedd4-2 and / or S444D Nedd4-2. Corresponding mutations cause Nedd4-2 can no longer be phosphorylated by Sgk1. Such antibodies can be used as a helpful tool to study mutants.
  • the preparation of the antibodies according to the invention is carried out by methods familiar to the person skilled in the art.
  • polyclonal or monoclonal antibodies can be made, with monoclonal antibodies being preferred because of their generally higher specificity.
  • the antibodies described can be used particularly advantageously in the diagnostic kit according to the invention. Furthermore, the antibodies described can also be used with great advantage in the use for detecting the expression and / or function of Sgk, PKB and / or Nedd. In this case, the antibodies can be used according to customary immunological methods. In particular, the aforementioned ELISA can be carried out with these antibodies.
  • composition preferably a pharmaceutical composition, containing at least one active agent which affects glucose transport, in particular intestinal and / or renal glucose transport, and optionally a pharmaceutically acceptable carrier.
  • the active ingredient particularly preferably influences at least one Sgk and / or PKB and / or at least one Nedd.
  • the active substance influences activators, inhibitors, regulators and / or biological precursors of a Sgk, in particular of Sgk1 and / or Sgk3, and / or PKB and / or a Nedd, in particular of Nedd4-2.
  • the active ingredient is a polynucleotide.
  • This polynucleotide may comprise or form an antisense sequence that reduces or inhibits the expression of the corresponding genes.
  • a corresponding polynucleotide may be chosen such that it inhibits the expression of the respective gene or genes by a so-called Dominant-Negative approach known to those skilled in the art or restricts the function of the corresponding gene products.
  • the polynucleotide may encode a peptide, preferably a polypeptide, which peptide influences the expression and / or function of a Sgk, in particular Sgk1 and / or Sgk3, and / or PKB and / or a Nedd, in particular Nedd4-2.
  • a Sgk in particular Sgk1 and / or Sgk3, and / or PKB and / or a Nedd, in particular Nedd4-2.
  • the active ingredient is the described peptide itself.
  • the active ingredient is a "small molecular compound", preferably a "small molecular compound” having a molecular weight ⁇ 1,000.
  • the active ingredient achieves an inhibition of at least one Sgk and / or PKB and / or a stimulation of at least one Nedd.
  • the active ingredient for the treatment of these diseases is particularly preferably at least one kinase inhibitor, preferably staurosporine and / or chelerythrine or one of its analogs, and / or at least one ligase activator.
  • the active ingredient preferably achieves a stimulation of at least one Sgk and / or PKB and / or an inhibition of at least one Nedd.
  • the active ingredient for increasing the glucose transport is an Sgk1 activator, in particular a growth factor, preferably IGF1, and / or insulin.
  • the active ingredient is a stimulant for the transcription of Sgk1 and / or Sgk3 and / or PKB, preferably at least one glucocorticoid, mineral corticoid, gonadotropin and / or cytokine, in particular TGF ⁇ .
  • transgenic animals having increased lipid deposition in adipose tissue.
  • People are excluded from this aspect.
  • Corresponding animals are of great interest, in particular for food production, because they start producing fat more quickly.
  • a mast can do a lot with these animals be done faster and more effectively.
  • the method for producing such animals is characterized in that the expression and / or function of Sglt, in particular Sglt1, is increased in these animals. This accelerates the intestinal absorption of glucose, resulting in a faster increase in plasma glucose concentration. As a result, more insulin is released, which eventually leads to a stimulation of lipid deposition in adipose tissue.
  • sglt in particular sglt1
  • sglt is overexpressed in the animal for this purpose. This is done, for example, by introducing appropriate gene constructs, in particular vectors, which carry correspondingly strong promoters, which are functionally preceded by a corresponding sglt sequence.
  • Sgk in particular Sgk1 and / or Sgk3, and / or PKB is increased in expression and / or function.
  • the activity or the protein amount of Sglt, in particular Sglt1 is also increased in the end result, so that the glucose transport is increased.
  • the corresponding genes can be overexpressed using current molecular biological methods.
  • gene constructs can also be introduced or integrated into the organism which express corresponding constitutively active mutants. Particularly preferred in this case are the mutants S422D sgk1 and / or T308D, S473D PKB.
  • Corresponding mutants are independent in their activity of other activating enzymes, in particular kinases, and therefore constantly active. They inhibit the degradation of Sglt caused by the ubiquitin ligase Nedd, in particular Nedd4-2, in particular Sglt1, so that as a result the glucose transport is increased.
  • the ubiquitin ligase Nedd in particular Nedd4-2, is reduced in its expression and / or function. This also causes an increase in the glucose transport by a reduced degradation of Sglt, in particular Sglt1.
  • a corresponding reduction in the expression and / or function of Nedd can also be achieved by conventional molecular biological methods, such as antisense or dominant negative approaches. It is particularly preferred to stably integrate suitable mutations of nedd, in particular of nedd4-2, into the organism or to switch off the native gene for Nedd in order to reduce or inhibit the expression of this enzyme in the long term. Corresponding procedures are known to the person skilled in the art.
  • Nedd4-2 it is particularly preferred in this case to insert at least one inactivating mutation in Nedd, in particular in Nedd4-2.
  • the mutations S338D nedd4-2 and / or S444D nedd4-2 can be used with great advantage. Animals producible by the method are also included.
  • Activation of serum- and glucocorticoid-regulated protein kinase by agonists that activate phosphatidylinositide 3-kinase is mediated by 3-phosphoinositide-dependent protein kinase-1 (PDK1) and PDK2.
  • PDK1 3-phosphoinositide-dependent protein kinase-1
  • the oocytes were injected with 5ng of human sglt1, 7.5ng of human sgk1, K127N sgk1, S422D sgk1, sgk3, PKB or T308D, S473D PKB and / or 5ng of Xenopus nedd4-2.
  • Control cells were injected with water. Electrophysiological experiments were performed at room temperature 3 days after injection of the respective cRNAs.
  • the control bath solution (ND 96) contained 96mM NaCl, 2mM KCl, 1.8mM CaCl 2 , 1mM MgCl 2 and 5mM HEPES, pH 7.4. All substances were used at the concentrations indicated. The final solutions were titrated with HCl or NaOH to the indicated pH and pH 7.4, respectively. The flow rate of the superfusion solution was 20 ml / min and achieved a complete solution change within 10 s.
  • n is the number of oocytes examined. All experiments were performed in at least three different groups of oocytes. In all repetitions qualitatively similar data were obtained. The results were tested for significant differences with Student t-test. Only results with P ⁇ 0.05 were used as statistically significant.
  • SNP single nucleotide polymorphism
  • S473D PKB and Sgk1 stimulated the glucose-induced current and reversed the effect of Nedd4-2.
  • the body mass index of twins was correlated with polymorphisms of the sgk1 gene.
  • twin studies show that the same polymorphism associated with increased blood pressure is also associated with a higher body mass index.

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EP03732526A 2002-06-04 2003-06-04 Sgk und nedd als diagnostische und therapeutische targets Expired - Lifetime EP1523571B1 (de)

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DE10225844 2002-06-04
DE10225844A DE10225844A1 (de) 2002-06-04 2002-06-04 sgk und nedd als diagnostische und therapeutische targets
PCT/EP2003/005847 WO2003102206A2 (de) 2002-06-04 2003-06-04 Sgk und nedd als diagnostische und therapeutische targets

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EP1523571A2 EP1523571A2 (de) 2005-04-20
EP1523571B1 true EP1523571B1 (de) 2008-07-09

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US (1) US20060121465A1 (zh)
EP (1) EP1523571B1 (zh)
JP (1) JP2005528113A (zh)
CN (2) CN100406570C (zh)
AT (1) ATE400665T1 (zh)
AU (1) AU2003238462A1 (zh)
BR (1) BRPI0311695A2 (zh)
CA (1) CA2487730A1 (zh)
DE (2) DE10225844A1 (zh)
MX (1) MXPA04012061A (zh)
PL (1) PL374083A1 (zh)
RU (1) RU2004139030A (zh)
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Publication number Priority date Publication date Assignee Title
DE10305212A1 (de) * 2003-02-07 2004-08-19 Florian Prof. Dr.med. Lang Verwendung der sgk-Genfamilie zur Diagnose und zur Therapie von Katarakt und Glaukom
DE10305213A1 (de) * 2003-02-07 2004-08-26 Florian Prof. Dr.med. Lang Verwendung eines neuen Polymorphismus im hsgk1-Gen zur Diagnose der Hypertonie und Verwendung der sgk-Genfamilie zur Diagnose und Therapie des Long-Q/T-Syndroms
WO2005118832A2 (en) * 2004-06-01 2005-12-15 Bayer Healthcare Ag Diagnostics and therapeutics for diseases associated with serum/glucocorticoid regulated kinase-like protein (sgkl)
DE102008029072A1 (de) * 2008-06-10 2009-12-17 Lang, Florian, Prof. Dr.med. Sgk3 als therapeutisches und diagnostisches Target für Alterserkrankungen
AU2009286380B2 (en) 2008-08-28 2011-09-15 Pfizer Inc. Dioxa-bicyclo[3.2.1.]octane-2,3,4-triol derivatives
ES2527179T3 (es) 2009-11-02 2015-01-21 Pfizer Inc. Derivados de dioxa-biciclo[3.2.1]octano-2,3,4-triol
US20140120111A1 (en) 2011-05-19 2014-05-01 The Johns Hopkins University Treatment of autoimmune disorders and infections using antagonists of sgk1 activity
CN104673762B (zh) * 2015-01-19 2017-10-20 江苏大学 抗泛素连接酶Nedd4‑1的特异性抗体及其应用
CN105535977A (zh) * 2015-12-30 2016-05-04 南方医科大学 Nedd4-2在帕金森病治疗中的应用
CN107875153A (zh) * 2017-11-16 2018-04-06 上海壹志医药科技有限公司 去甲白屈菜红碱的药物用途

Family Cites Families (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4952567A (en) * 1988-05-09 1990-08-28 City Of Hope Inhibition of lipogenesis
DE4218669C1 (zh) * 1992-06-05 1993-09-02 Max-Planck-Gesellschaft Zur Foerderung Der Wissenschaften Ev, 3400 Goettingen, De
WO1999064062A1 (en) * 1998-06-08 1999-12-16 Pharmacia & Upjohn Ab New therapeutic use of pkb (proteine kinase b) enhancers
US6486299B1 (en) * 1998-09-28 2002-11-26 Curagen Corporation Genes and proteins predictive and therapeutic for stroke, hypertension, diabetes and obesity
DE19917990A1 (de) * 1999-04-20 2000-11-02 Florian Lang Arzneimittel enthaltend Hemmstoffe der zellvolumenregulierten humanen Kinase h-sgk
CN1327054A (zh) * 2000-06-05 2001-12-19 上海博德基因开发有限公司 一种新的多肽——人类Nedd－4泛醌蛋白连接酶WWP28.8和编码这种多肽的多核苷酸

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WO2003102206A3 (de) 2005-02-24
CN1668762A (zh) 2005-09-14
CN101241127A (zh) 2008-08-13
US20060121465A1 (en) 2006-06-08
JP2005528113A (ja) 2005-09-22
PL374083A1 (en) 2005-09-19
CN100406570C (zh) 2008-07-30
ZA200409788B (en) 2005-06-29
MXPA04012061A (es) 2005-03-07
WO2003102206A2 (de) 2003-12-11
DE50310113D1 (de) 2008-08-21
AU2003238462A1 (en) 2003-12-19
ATE400665T1 (de) 2008-07-15
CA2487730A1 (en) 2003-12-11
RU2004139030A (ru) 2006-01-20
EP1523571A2 (de) 2005-04-20
DE10225844A1 (de) 2003-12-18

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